Pyrrolo[2,3-d]pyrimidine and their use as purinergic receptor antagonists

ABSTRACT

Use of a compound of the formula (I) wherein R 1  is selected from alkyl, alkoxy, aryloxy, alkylthio, arylthio, aryl, halogen, CN, NR 7 R 8 , NR 6 COR 7 , NR 6 CO 2 R 9  and NR 6 SO 2 R 9 ; R 2  is selected from aryl attached via an unsaturated carbon; R 3  and R 4  are independently selected from H, alkyl, halogen, alkoxy, alkylthio, CN and NR 7 R 8 ; R 5  is selected from H, acyclic alkyl, COR 6 , CONR 7 R 8 , CONR 6 NR 7 R 8 , CO 2 R 9  and SO 2 R 9 ; R 6 , R 7  and R 8  are independently selected from H, alkyl and aryl or where R 7  and R 8  are in an NR 7 R 8  group R 7  and R 8  may be linked to form a hererocyclic group, or where R 6 , R 7  and R 8  are in a (CONR 6 NR 7 R 8 ) group, R 6  and R 7  may be linked to form a hererocyclic group; and R 9  is selected from alkyl and aryl, or a pharmaceutically acceptable salt thereof or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly A 2A  receptors, may be beneficial, particularly wherein said disorder is a movement disorder such as Parkinson&#39;s disease or said disorder is depression, cognitive or memory impairment, acute or chronic pain, ADHD or narcolepsy, or for neuroprotection in a subject; compounds of formula (I) for use in therapy; and novel compounds of formula (I) per se

The present invention relates to pyrrolo[2,3-d]pyrimidin derivatives andtheir use in therapy. In particular, the present invention relates tothe treatment of disorders in which the reduction of purinergicneurotransmission could be beneficial. The invention relates inparticular to blockade of adenosine receptors and particularly adenosineA_(2A) receptors, and to the treatment of movement disorders such asParkinson's disease.

Movement disorders constitute a serious health problem, especiallyamongst the elderly sector of the population. These movement disordersare often the result of brain lesions. Disorders involving the basalganglia which result in movement disorders include Parkinson's disease,Huntington's chorea and Wilson's disease. Furthermore, dyskinesias oftenarise as sequelae of cerebral ischaemia and other neurologicaldisorders.

There are four classic symptoms of Parkinson's disease: tremor,rigidity, akinesia and postural changes. The disease is also commonlyassociated with depression, dementia and overall cognitive decline.Parkinson's disease has a prevalence of 1 per 1,000 of the totalpopulation. The incidence increases to 1 per 100 for those aged over 60years. Degeneration of dopaminergic neurones in the substantia nigra andthe subsequent reductions in interstitial concentrations of dopamine inthe striatum are critical to the development of Parkinson's disease.Some 80% of cells from the substantia nigra need to be destroyed beforethe clinical symptoms of Parkinson's disease are manifested.

Current strategies for the treatment of Parkinson's disease are based ontransmitter replacement therapy (L-dihydroxyphenylacetic acid (L-DOPA)),inhibition of monoamine oxidase (e.g. Deprenyl®), dopamine receptoragonists (e.g. bromocriptine and apomorphine) and anticholinergics (e.g.benztrophine, orphenadrine). Transmitter replacement therapy inparticular does not provide consistent clinical benefit, especiallyafter prolonged treatment when “on-off” symptoms develop, and thistreatment has also been associated with involuntary movements ofathetosis and chorea, nausea and vomiting. Additionally currenttherapies do not treat the underlying neurodegenerative disorderresulting in a continuing cognitive decline in patients. Despite newdrug approvals, there is still a medical need in terms of improvedtherapies for movement disorders, especially Parkinson's disease. Inparticular, effective treatments requiring less frequent dosing,effective treatments which are associated with less severe side-effects,and effective treatments which control or reverse the underlyingneurodegenerative disorder, are required.

Blockade of A₂ adenosine receptors has recently been implicated in thetreatment of movement disorders such as Parkinson's disease (Richardson,P. J. et al., Trends Pharmacol. Sci. 1997, 18, 338–344) and in thetreatment of cerebral ischaemia (Gao, Y. and Phillis, J. W., Life Sci.1994, 55, 61–65). The potential utility of adenosine A_(2A) receptorantagonists in the treatment of movement disorders such as Parkinson'sDisease has recently been reviewed (Mally, J. and Stone, T. W., CNSDrugs, 1998, 10, 311–320).

Adenosine is a naturally occurring purine nucleoside which has a widevariety of well-documented regulatory functions and physiologicaleffects. The central nervous system (CNS) effects of this endogenousnucleoside have attracted particular attention in drug discovery, owingto the therapeutic potential of purinergic agents in CNS disorders(Jacobson, K. A. et al., J. Med. Chem. 1992, 35, 407–422). Thistherapeutic potential has resulted in considerable recent researchendeavour within the field of adenosine receptor agonists andantagonists (Bhagwhat, S. S.; Williams, M. Exp. Opin. Ther. Patents1995, 5,547–558).

Adenosine receptors represent a subclass (P₁) of the group of purinenucleotide and nucleoside receptors known as purinoreceptors. The mainpharmacologically distinct adenosine receptor subtypes are known as A₁,A_(2A), A_(2B) (of high and low affinity) and A₃ (Fredholm, B. B., etal., Pharmacol. Rev. 1994, 46, 143–156). The adenosine receptors arepresent in the CNS (Fredholm, B. B., News Physiol. Sci., 1995, 10,122–128).

The design of P₁ receptor-mediated agents has been reviewed (Jacobson,K. A., Suzuki, F., Drug Dev. Res., 1997, 39, 289–300; Baraldi, P. G. etal., Curr. Med. Chem. 1995, 2, 707–722), and such compounds are claimedto be useful in the treatment of cerebral ischemia or neurodegenerativedisorders, such as Parkinson's disease (Williams, M. and Burnstock, G.Purinergic Approaches Exp. Ther. (1997), 3–26. Editor: Jacobson, KennethA.; Jarvis, Michael F. Publisher: Wiley-Liss, New York, N.Y.)

It has been speculated that xanthine derivatives such as caffeine mayoffer a form of treatment for attention-deficit hyperactivity disorder(ADHD). A number of studies have demonstrated a beneficial effect ofcaffeine on controlling the symptoms of ADHD (Garfinkel, B. D. et al.,Psychiatry, 1981, 26, 395–401). Antagonism of adenosine receptors isthought to account for the majority of the behavioural effects ofcaffeine in humans and thus blockade of adenosine A_(2A) receptors mayaccount for the observed effects of caffeine in ADHD patients. Thereforea selective A_(2A) receptor antagonist may provide an effectivetreatment for ADHD but without the unwanted side-effects associated withcurrent therapy.

Adenosine receptors have been recognised to play an important role inregulation of sleep patterns, and indeed adenosine antagonists such ascaffeine exert potent stimulant effects and can be used to prolongwakefulness (Porkka-Heiskanen, T. et al., Science, 1997, 276,1265–1268). Recent evidence suggests that a substantial part of theactions of adenosine in regulating sleep is mediated through theadenosine A_(2A) receptor (Satoh, S., et al., Proc. Natl. Acad. Sci.,USA, 1996). Thus, a selective A_(2A) receptor antagonist may be ofbenefit in counteracting excessive sleepiness in sleep disorders such ashypersomnia or narcolepsy.

It has recently been observed that patients with major depressiondemonstrate a blunted response to adenosine agonist-induced stimulationin platelets, suggesting that a dysregulation of A_(2A) receptorfunction may occur during depression (Berk, M. et al, 2001, Eur.Neuropsychophannacol. 11, 183–186). Experimental evidence in animalmodels has shown that blockade of A_(2A) receptor function confersantidepressant activity (El Yacoubi, M et al. Br. J. Pharmacol. 2001,134, 68–77). Thus, A_(2A) receptor antagonists may offer a novel therapyfor the treatment of major depression and other affective disorders inpatients.

The pharmacology of adenosine A_(2A) receptors has been reviewed(Ongini, E.; Fredholm, B. B. Trends Pharmacol. Sci. 1996, 17(10),364–372). One potential underlying mechanism in the aforementionedtreatment of movement disorders by the blockade of A₂ adenosinereceptors is the evidence of a functional link between adenosine A_(2A)receptors to dopamine D₂ receptors in the CNS. Some of the early studies(e.g. Ferre, S. et al., Stimulation of high-affinity adenosine A₂receptors decreases the affinity of dopamine D₂ receptors in ratstriatal membranes. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 7238–41)have been summarised in two more recent articles (Fuxe, K. et al.,Adenosine Adenine Nucleotides Mol. Biol. Integr. Physiol., [Proc. Int.Symp.], 5th (1995), 499–507. Editors: Belardinelli, Luiz; Pelleg, Amir.Publisher: Kluwer, Boston, Mass.; Ferre, S. et al., Trends Neurosci.1997, 20, 482–487).

As a result of these investigations into the functional role ofadenosine A_(2A) receptors in the CNS, especially in vivo studieslinking A₂ receptors with catalepsy (Ferre et al., Neurosci. Lett. 1991,130, 162–4; Mandhane, S. N. et al., Eur. J. Pharmacol. 1997, 328,135–141) investigations have been made into agents which selectivelybind to adenosine A_(2A) receptors as potentially effective treatmentsfor Parkinson's disease.

While many of the potential drugs for treatment of Parkinson's diseasehave shown benefit in the treatment of movement disorders, an advantageof adenosine A_(2A) antagonist therapy is that the underlyingneurodegenerative disorder may also be treated. The neuroprotectiveeffect of adenosine A_(2A) antagonists has been reviewed (Ongini, E.;Adami, M.; Ferri, C.; Bertorelli, R., Ann. N. Y. Acad. Sci. 1997,825(Neuroprotective Agents), 30–48). In particular, compelling recentevidence suggests that blockade of A_(2A) receptor function confersneuroprotection against MPTP-induced neurotoxicity in mice (Chen, J-F.,J. Neurosci. 2001, 21, RC143). In addition, several recent studies haveshown that consumption of dietary caffeine, a known adenosine A_(2A)receptor antagonist, is associated with a reduced risk of Parkinson'sdisease in man (Ascherio, A. et al, Ann Neurol., 2001, 50, 56–63; Ross GW, et al., JAMA, 2000, 283, 2674–9). Thus, A_(2A) receptor antagonistsmay offer a novel treatment for conferring neuroprotection inneurodegenerative diseases such as Parkinson's disease.

Xanthine derivatives have been disclosed as adenosine A₂ receptorantagonists as useful for treating various diseases caused byhyperfunctioning of adenosine A₂ receptors, such as Parkinson's disease(see, for example, EP-A-565377).

One prominent xanthine-derived adenosine A_(2A) selective antagonist isCSC [8-(3-chlorostyryl)caffeine] (Jacobson et al., FEBS Lett., 1993,323, 141–144).

Theophylline (1,3-dimethylxanthine), a bronchodilator drug which is amixed antagonist at adenosine A₁ and A_(2A) receptors, has been studiedclinically. To determine whether a formulation of this adenosinereceptor antagonist would be of value in Parkinson's disease an opentrial was conducted on 15 Parkinsonian patients, treated for up to 12weeks with a slow release oral theophylline preparation (150 mg/day),yielding serum theophylline levels of 4.44 mg/L after one week. Thepatients exhibited significant improvements in mean objective disabilityscores and 11 reported moderate or marked subjective improvement (Mally,J., Stone, T. W. J. Pharm. Pharmacol. 1994, 46, 515–517).

KF 17837 [(E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine] isa selective adenosine A_(2A) receptor antagonist which on oraladministration significantly ameliorated the cataleptic responsesinduced by intracerebroventricular administration of an adenosine A_(2A)receptor agonist, CGS 21680. KF 17837 also reduced the catalepsy inducedby haloperidol and reserpine. Moreover, KF 17837 potentiated theanticataleptic effects of a subthreshold dose of L-DOPA plusbenserazide, suggesting that KF 17837 is a centrally active adenosineA_(2A) receptor antagonist and that the dopaminergic function of thenigrostriatal pathway is potentiated by adenosine A_(2A) receptorantagonists (Kanda, T. et al., Eur. J. Pharmacol. 1994, 256, 263–268).The structure activity relationship (SAR) of KF 17837 has been published(Shimada, J. et al., Bioorg. Med. Chem. Lett. 1997, 7, 2349–2352).Recent data has also been provided on the A_(2A) receptor antagonistKW-6002 (Kuwana, Y et al., Soc. Neurosci. Abstr. 1997, 23, 119.14; andKanda, T. et al., Ann. Neurol. 1998, 43(4), 507–513).

New non-xanthine structures sharing these pharmacological propertiesinclude SCH 58261 and its derivatives (Baraldi, P. G. et al.,Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyriridine Derivatives: Potent andSelective A_(2A) Adenosine Antagonists. J. Med. Chem. 1996, 39,1164–71). SCH 58261(7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) is reported as effective in the treatment of movementdisorders (Ongini, E. Drug Dev. Res. 1997, 42(2), 63–70) and has beenfollowed up by a later series of compounds (Baraldi, P. G. et al., J.Med. Chem. 1998, 41(12), 2126–2133).

The foregoing discussion indicates that a potentially effectivetreatment for movement disorders in humans would comprise agents whichact as antagonists at adenosine A_(2A) receptors.

It has now been found that pyrrolo[2,3-d]pyrimidine derivatives, whichare structurally unrelated to known adenosine receptor antagonists,exhibit unexpected antagonist binding affinity at adenosine (P₁)receptors, and in particular at the adenosine A_(2A) receptor. Suchcompounds may therefore be useful for the treatment of disorders inwhich the blocking of purine receptors, particularly adenosine receptorsand more particularly adenosine A_(2A) receptors, may be beneficial. Inparticular such compounds may be suitable for the treatment of movementdisorders, such as disorders of the basal ganglia which result indyskinesias. Disorders of particular interest in the present inventioninclude Parkinson's disease, Alzheimer's disease, spasticity,Huntington's chorea and Wilson's disease.

Such compounds may also be particularly suitable for the treatment ofdepression, cognitive or memory impairment including Alzheimer'sdisease, acute or chronic pain, ADHD, narcolepsy or for neuroprotection.

According to the present invention there is provided the use of acompound of formula (I):

wherein

-   R₁ is selected from alkyl, alkoxy, aryloxy, alkylthio, arylthio,    aryl, halogen, CN, NR₇R₈, NR₆COR₇, NR₆CONR₇R₈, NR₆CO₂R₉ and    NR₆SO₂R₉;-   R₂ is selected from aryl attached via an unsaturated carbon;-   R₃ and R₄ are independently selected from H, alkyl, halogen, alkoxy,    alkylthio, CN and NR₇R₈;-   R₅ is selected from H, acyclic alkyl, COR₆, CONR₇R₈, CONR₆NR₇R₈,    CO₂R₉ and SO₂R₉;-   R₆, R₇ and R₈ are independently selected from H, alkyl and aryl or    where R₇ and R₈ are in an NR₇R₈ group, R₇ and R₈ may be linked to    form a heterocyclic group, or where R₆, R₇ and R₈ are in a    (CONR₆NR₇R₈) group, R₆ and R₇ may be linked to form a heterocyclic    group; and-   R₉ is selected from alkyl and aryl,-   or a pharmaceutically acceptable salt or prodrug thereof, in the    manufacture of a medicament for the treatment or prevention of a    disorder in which the blocking of purine receptors, particularly    adenosine receptors and more particularly A_(2A) receptors, may be    beneficial.

As used herein the term “alkyl”, unless otherwise stated, means abranched or unbranched, cyclic or acyclic, saturated or unsaturated(e.g. alkenyl or alkynyl) hydrocarbyl radical which may be substitutedor unsubstituted. Where cyclic, the alkyl group is preferably C₃ to C₁₂,more preferably C₅ to C₁₀, more preferably C₅, C₆ or C₇. Where acyclic,the alkyl group is preferably C₁ to C₁₀, more preferably C₁ to C₆, morepreferably methyl, ethyl, propyl (n-propyl or isopropyl), butyl(n-butyl, isobutyl or tertiary-butyl) or pentyl (including n-pentyl andiso-pentyl), more preferably methyl. It will be appreciated thereforethat the term “alkyl” as used herein, unless otherwise stated, includesalkyl (branched or unbranched), alkenyl (branched or unbranched),alkynyl (branched or unbranched), cycloalkyl, cycloalkenyl andcycloalkynyl.

As used herein, the term “lower alkyl” means methyl, ethyl, propyl(n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).

As used herein, the term “aryl” means an aromatic group, such as phenylor naphthyl (preferably phenyl), or a heteroaromatic group containingone or more heteroatom(s) preferably selected from N, O and S, such aspyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl,thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl,imidazolyl, pyrimidinyl, indolyl, pyrazinyl or indazolyl.

As used herein, the term “heteroaryl” means an aromatic group containingone or more heteroatom(s) preferably selected from N, O and S, such aspyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl,thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl,imidazolyl, pyrimidinyl, indolyl, pyrazinyl or indazolyl.

As used herein, the term “non-aromatic heterocyclyl” means anon-aromatic cyclic group containing one or more heteroatom(s)preferably selected from N, O and S, such as a cyclic amino group(including aziridinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl,morpholinyl) or a cyclic ether (including tetrahydrofuranyl).

As used herein, the term “alkoxy” means alkyl-O—. As used herein, theterm “aryloxy” means aryl-O—.

As used herein, the term “halogen” means a fluorine, chlorine, bromineor iodine radical.

As used herein, the term “ortho,ortho-disubstituted aryl groups” refersto aryl groups which are substituted in both ortho positions of the arylgroup relative to the point of attachment of the aryl group to thepyrimidine ring.

As used herein, the term “prodrug” means any pharmaceutically acceptableprodrug of a compound of the present invention.

Where any of R₁ to R₁₅ is selected from alkyl, alkoxy and thioalkyl, inaccordance with formula (I) as defined above, then that alkyl group, orthe alkyl group of the alkoxy or thioalkyl group, may be substituted orunsubstituted. Where any of R₁ to R₁₅ are selected from aryl, aryloxyand thioaryl, in accordance with formula (I) as defined above, then saidaryl group, or the aryl group of the aryloxy or thioaryl group, may besubstituted or unsubstituted. Where R₇ and R₈, or R₆ and R₇, are linkedto form a heterocyclic group, the heterocyclic group may be substitutedor unsubstituted. Where substituted, there will generally be 1 to 3substituents present, preferably 1 substituent. Substituents mayinclude:

Carbon-containing groups such as alkyl, (e.g. substituted andunsubstituted phenyl (including aryl, (alkyl)phenyl, (alkoxy)phenyl,(alkyl- and aryl- sulfonylamino)phenyl and halophenyl), arylalkyl; (e.g.substituted and unsubstituted benzyl); halogen atoms and halogencontaining groups such as haloalkyl (e.g. trifluoromethyl), haloaryl(e.g. chlorophenyl); oxygen containing groups such as alcohols (e.g.hydroxy, hydroxyalkyl, hydroxyaryl, (aryl)(hydroxy)alkyl), ethers (e.g.alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl, alkoxyaryl, aryloxyaryl),aldehydes (e.g. carboxaldehyde), ketones (e.g. alkylcarbonyl,arylcarbonyl, alkylcarbonylalkyl, alkylcarbonylaryl, arylcarbonylalkyl,arylcarbonylaryl, arylalkylcarbonyl, arylalkylcarbonylalkyl,arylalkylcarbonylaryl) acids (e.g. carboxy, carboxyalkyl, carboxyaryl),acid derivatives (e.g. alkoxycarbonyl, aryloxycarbonyl, such as estersalkoxycarbonylalkyl, aryloxycarbonylalkyl, alkoxycarbonylaryl,aryloxycarbonylaryl, alkylcarbonyloxy, alkylcarbonyloxyalkyl), amides(e.g. aminocarbonyl, mono- or di-alkylaminocarbonyl,cyclicaminocarbonyl, aminocarbonylalkyl, mono- or di-alkylaminocarbonylalkyl, arylaminocarbonyl or arylalkylaminocarbonyl,alkylcarbonylamino, arylcarbonylamino or arylalkylcarbonylamino),carbamates (eg. alkoxycarbonylamino, aryloxycarbonylamino,arylalkyloxycarbonylamino, aminocarbonyloxy, mono- ordi-alkylaminocarbonyloxy, arylaminocarbonyloxy orarylalkylaminocarbonyloxy) and ureas (eg. mono- ordi-alkylaminocarbonylamino, arylaminocarbonylamino orarylalkylaminocarbonylamino); nitrogen containing groups such as amines(e.g. amino, mono- or dialkylamino, cyclicamino, arylamino, aminoalkyl,mono- or dialkylaminoalkyl), azides, nitriles (e.g. cyano, cyanoalkyl),nitro, sulfonamides (e.g. aminosulfonyl, mono- or di-alkylaminosulfonyl,mono- or di-arylaminosulfonyl, alkyl- or aryl- sulfonylamino, alkyl- oraryl-sulfonyl(alkyl)amino, alkyl- or aryl-sulfonyl(aryl)amino); sulfurcontaining groups such as thiols, (e.g. alkylthio, alkylsulfinyl,alkylsulfonyl, thioethers, alkylthioalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, sulfoxides, arylthio, arylsulfinyl, arylsulfonyl,arylthioalkyl, and sulfones arylsulfinylalkyl, arylsulfonylalkyl) andheterocyclic groups containing one or more, preferably one, heteroatom,(e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl,azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl,pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl,pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl, morpholinyl,thianaphthyl, benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl,isoindolyl, indazolyl, indolinyl, 7- azaindolyl, benzopyranyl,coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, naphthridinyl,cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl,chromenyl, chromanyl, isochromanyl, phthalazinyl and carbolinyl).

Where any of R₁ to R₁₅ is selected from aryl or from an aryl-containinggroup such as aryloxy or arylthio, preferred substituent group(s) areselected from halogen, alkyl (substituted or unsubstituted; and wheresubstituted particularly from alkoxyalkyl, hydroxyalkyl, aminoalkyl andhaloalkyl), hydroxy, alkoxy, CN, NO₂, amines (including amino, mono- anddialkylamino), alkoxycarbonyl, aminocarbonyl, carboxamido, sulfonamido,alkoxycarbonylamino and aryl, and particularly from unsubstituted alkyl,substituted alkyl (including alkoxyalkyl and aminoalkyl), halogen andamines.

In one embodiment, where any of R₁ to R₁₅ is directly substituted by analkyl substituent group, or by an alkyl-containing substituent group(such as alkoxy or alkylcarbonylamino for example), then the alkylmoiety of the substituent group directly attached to any of R₁ to R₁₅may be further substituted by the substituent groups hereinbeforedescribed and particularly by halogen, hydroxy, alkoxy, CN, amines(including amino, mono- and di-alkyl amino) and aryl.

In a further embodiment, where any of R₁ to R₁₅ is directly substitutedby an aryl substitutent group, or by an aryl-containing substituentgroup (such as aryloxy or arylaminocarbonylamino for example), then thearyl moiety of the substituent group directly attached to any of R₁ toR₁₅ may be further substituted by the substituent groups hereinbeforedescribed and particularly by halogen, alkyl (substituted orunsubstituted; and where substituted particularly from alkoxyalkyl,hydroxyalkyl, aminoalkyl and haloalkyl), hydroxy, alkoxy, CN, NO₂,amines (including amino, mono- and di-alkylamino), alkoxycarbonyl,aminocarbonyl, carboxamido, sulfonamido, alkoxycarbonylamino and aryl.In a further embodiment, said aryl moiety is substituted by halogen,alkyl (including CF₃), hydroxy, alkoxy, CN, amines (including amino,mono- and di-alkyl amino) and NO₂. In a further embodiment, said arylmoiety is substituted by unsubstituted alkyl, substituted alkyl(particularly alkoxyalkyl and aminoalkyl), halogen and amines.

The terms “directly substituted” and “directly attached”, as usedherein, mean that the substituent group is bound directly to any of R₁to R₁₅ without any intervening divalent atoms or groups.

In the compounds of formula (I), R₁ is selected from alkyl (includingbranched and unbranched alkyl, substituted and unsubstituted alkyl, andcyclic and acyclic alkyl), alkoxy, aryloxy, alkylthio, arylthio, aryl(including heteroaryl), halogen, CN, NR₇R₈ (including NH₂,mono-alkylamino and di-alkylamino), NR₆COR₇, NR₆CONR₇R₈, NR₆CO₂R₉ andNR₆SO₂R₉.

Where R₁ is selected from alkyl, alkoxy and alkylthio, then said alkylgroup or the alkyl group of the alkoxy or alkylthio is preferablyselected from C₁₋₆ alkyl (including branched and unbranched alkyl,substituted and unsubstituted alkyl, and cyclic and acyclic alkyl),preferably saturated C₁₋₆ alkyl, and more preferably lower allyl. In oneembodiment, R₁ is selected from substituted alkyl, particularlyhaloalkyl (including CF₃) and arylalkyl (including heteroarylalkyl), andparticularly haloalkyl (including CF₃).

Where R₁ is selected from NR₆COR₇, NR₆CONR₇R₈, NR₆CO₂R₉ and NR₆SO₂R₉,preferably R₆ is H or alkyl, and preferably H.

It is preferred that R₁ is selected from alkyl, alkoxy, thioalkyl, NR₇R₈(including NH₂), NR₆COR₇, NR₆CONR₇R₈, NR₆CO₂R₉ and NR₆SO₂R₉, andpreferably from NR₇R₈ (including NH₂), NR₆COR₇, NR₆CONR₇R₈, NR₆CO₂R₉ andNR₆SO₂R₉, more preferably from NR₇R₈ (including NH₂), and morepreferably from NH₂.

In the compounds of formula (I), R₂ is selected from aryl (includingheteroaryl) attached via an unsaturated carbon atom. R₂ may besubstituted or unsubstituted. Preferably, R₂ is a 5- or 6memberedmonocyclic aryl group.

It is preferred that R₂ is not an ortho,ortho-disubstituted aryl group.Preferably, R₂ is not substituted at an ortho position relative to thepoint of attachment of the aryl group to the pyrimidine ring.

Preferably, R₂ is selected from substituted or unsubstituted heteroarylattached via an unsaturated carbon atom.

Preferably, R₂ is a heteroaryl group which is attached to the pyrimidinering of formula (I) such that at least one heteroatom is adjacent to theunsaturated carbon atom attached to the pyrimidine ring. Preferably, R₂is an N, O or S-containing heteroaryl group, containing one or moreheteroatom(s) selected from N, O and S.

In a preferred embodiment, R₂ is selected from furyl (including2-furyl), thienyl (including 2-thienyl), pyridyl (including 2-pyridyl),thiazolyl (including 2- and 5-thiazolyl), pyrazolyl (including3-pyrazolyl), triazolyl (including 4-triazolyl), pyrrolyl (including2-pyrrolyl) and oxazolyl (including 5-oxazolyl). In a furtherembodiment, R₂ is selected from 2-furyl, 2-thienyl, 2-thiazolyl,2-pyridyl, 3-pyrazolyl, 2-pyrrolyl, 4-triazolyl and 5-oxazolyl. In afurther preferred embodiment, R₂ is selected from furyl, thienyl,pyridyl, thiazolyl and pyrazolyl, and particularly from 2-furyl,2-thienyl, 2-thiazolyl, 2-pyridyl and 3-pyrazolyl. In a furtherembodiment, R₂ is selected from furyl, thienyl and pyridyl, preferably2-furyl, 2-thienyl and 2-pyridyl, and more preferably from 2-furyl.

In a particularly preferred embodiment, R₂ is furyl, and preferably2-furyl.

In the compounds of formula (I), R₃ and R₄ are independently selectedfrom H, alkyl (including branched and unbranched alkyl, substituted andunsubstituted allyl, and cyclic and acyclic alkyl), halogen, alkoxy,alkylthio, CN and NR₇R₈.

Where R₃ and R₄ are independently selected from alkyl, alkoxy andalkylthio, then said alkyl group or the alkyl group of the alkoxy oralkylthio is preferably selected from C₁₋₆ alkyl (including branched andunbranched alkyl, substituted and unsubstituted alkyl, and cyclic andacyclic alkyl), preferably saturated C₁₋₆ alkyl, and more preferablylower allyl.

Preferably, R₃ and R₄ are independently selected from hydrogen.

In the compounds of formula (I), R₅ is selected from H, acyclic alkyl(including branched and unbranched alkyl, and substituted andunsubstituted alkyl), COR₆, CONR₇R₈, CONR₆NR₇R₈, CO₂R₉ and SO₂R₉.

Where R₅ is selected from CONR₇R₈, R₇ and R₈ are selected from H, alkyl(including substituted alkyl such as arylalkyl (includingheteroarylalkyl)) and aryl (including heteroaryl) or R₇ and R₈ may belinked to form a heterocyclic ring. In a preferred embodiment, R₇ and R₈are selected from H, unsubstituted alkyl, arylalkyl (includingheteroarylalkyl) and aryl (including heteroaryl). Said aryl groups maybe substituted or unsubstituted. In a preferred embodiment one of R₇ andR₈ is hydrogen. In a further preferred embodiment, R₇ is H and R₈ isselected from arylalkyl (including heteroarylalkyl), preferablyarylmethyl (including heteroarylmethyl).

Where R₅ is selected from acyclic alkyl, it is preferably C₁₋₆ acyclicalkyl (including alkenyl and alkynyl). In one embodiment, R₅ is selectedfrom C₁₋₆ saturated acyclic alkyl, preferably lower alkyl.

In one embodiment, R₅ is selected from substituted acyclic alkyl(including saturated acyclic alkyl and alkenyl). Preferred substituentsare aryl (including heteroaryl), cycloalkyl, non-aromatic heterocyclyl,CO₂R₆, CONR₇R₈, CONR₆NR₇R₈ and C(═NR₆)NR₇R₈, preferably aryl (includingheteroaryl) and CONR₇R₈, and more preferably aryl (includingheteroaryl).

Where R₅ is selected from acyclic alkyl substituted by aryl (includingheteroaryl), the aryl (including heteroaryl) group may be substituted orunsubstituted, preferably substituted. Preferred aryl groups arediscussed below with regard to the group R₁₂. Preferably, thearyl-substituted acyclic alkyl is an aryl-substituted methyl group.

In one embodiment, R₅ is selected from (CR₁₀R₁₁)_(n)R₁₂ wherein n is 1to 6 (preferably n is 1), R₁₀ and R₁₁ are independently selected from H,alkyl and aryl, and R₁₂ is selected from aryl (including heteroaryl),cycloalkyl, non-aromatic heterocyclic, CO₂R₆, CONR₇R₈, CONR₆NR₇R₈ andC(═NR₆)NR₇R₈. Preferably, R₁₂ is selected from aryl (includingheteroaryl) and CONR₇R₈, and more preferably from aryl (includingheteroaryl). Preferably R₁₀ and R₁₁ are independently selected from Hand alkyl, more preferably H.

Where R₁₂ is selected from CONR₇R₈, R₇ and R₈ are selected from H, alkyl(including substituted alkyl such as arylalkyl (includingheteroarylalkyl)) and aryl (including heteroaryl) or R₇ and R₈ may belinked to form a heterocyclic ring. In one embodiment, R₇ and R₈ areselected from H, unsubstituted alkyl, arylalkyl (includingheteroarylalkyl) and aryl (including heteroaryl). Said aryl groups maybe substituted or unsubstituted. In a preferred embodiment one of R₇ andR₈ is hydrogen.

Where R₁₂ is selected from aryl (including heteroaryl), the aryl groupmay be unsubstituted or substituted, and is preferably substituted. In apreferred embodiment, R₁₂ is selected from mono-, di- or tri-substitutedaryl (including heteroaryl) groups. Where R₁₂ is heteroaryl, R₁₂ ispreferably selected from mono or bicyclic heteroaryl groups, morepreferably from pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl,preferably 2-pyridyl), indolyl (including 2-indolyl, 3-indolyl,4-indolyl, 5-indolyl, 6-indolyl and 7-indolyl), furyl (including 2-furyland 3-furyl, preferably 2-furyl), thienyl (including 2-thienyl and3-thienyl, preferably 2-thienyl), isoindolyl, indolinyl, isoxazolyl,oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, quinolinyl,benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, indazolyl,benzodioxolyl and dihydrobenzofuranyl, more preferably from pyridyl(preferably 2-pyridyl), indolyl, furyl (preferably 2-furyl) and thienyl(preferably 2-thienyl), and most preferably from pyridyl (preferably2-pyridyl), furyl (preferably ²-furyl) and thienyl (preferably2-thienyl). Preferably, R₁₂ is selected from phenyl, thienyl, furyl andpyridyl, more preferably from phenyl, 2-thienyl, 2-furyl and 2-pyridyl.

In one embodiment, R₁₂ is selected from mono-, di- or tri-substitutedaryl (including heteroaryl) groups represented by the formulaAr(R₁₃)_(a)(R₁₄)_(b)(R₁₅)_(c) wherein Ar is an aryl (includingheteroaryl) group, preferably selected from the preferred aryl groupsdescribed above for R₁₂; wherein R₁₃, R₁₄ and R₁₅ are substituentgroup(s), the same or different; and wherein a, b and c are 0 or 1 suchthat a+b+c≧1.

The substituent groups R₁₃, R₁₄ and R₁₅ may be selected from any of thesubstituent groups described herein above.

In a preferred embodiment, R₁₃, R₁₄ and R₁₅ are selected from NR₇R₈(including NH₂, and NHR₇) alkyl (substituted or unsubstituted;preferably C₁₋₆ acyclic alkyl), alkoxy (including fluoroalkoxy), halogen(including F, Cl, Br and I), NO₂, CN, hydroxy, NHOH, CHO, CONR₇R₈,CO₂R₇, NR₆COR₇ (preferably NHCOR₇), NR₆CO₂R₉ (preferably NHCO₂R₉),NR₆SO₂R₉ (preferably NHSO₂R₉), OCO₂R₉ and aryl (including heteroaryl).

In a more preferred embodiment, R₁₃, R₁₄ and R₁₅ are selected from NR₇R₈(including NH₂ and NHR₇), alkyl (substituted or unsubstituted; andpreferably C₁₋₆ acyclic saturated alkyl) and halogen (preferably P orCl, particularly F).

In a particularly preferred embodiment, R₁₃, R₁₄ and R₁₅ are selectedfrom NR₇R₈ (including NH₂ and NHR₇, preferably NH₂) and allyl(substituted or unsubstituted; preferably C₁₋₆ acyclic saturated alkyl).

Where R₁₃, R₁₄ and R₁₅ are selected from substituted alkyl, said alkylis preferably selected from alkoxyalkyl, hydroxyalkyl, aminoalkyl(including NH₂-alkyl, mono-alkylaminoalkyl and di-alkylaminoalkyl),haloalkyl (particularly fluoroalkyl (including CF₃)), cyanoalkyl,alkylthioalkyl, alkylcarboxyaminoalkyl, alkoxycarbonylaminoalkyl andalkylsulfonylamino, more preferably from alkoxyalkyl, hydroxyalkyl,aminoalkyl and haloalkyl (particularly fluoroalkyl (including CF₃)) andmost preferably from alkoxyalkyl and aminoalkyl.

In one embodiment, the substituent groups R₁₃, R₁₄ and R₁₅ are selectedfrom halogen, alkyl (including CF₃), hydroxy, alkoxy, alkylthio, CN,amines (including amino, mono- and di-alkyl amino) and NO₂.

In a preferred embodiment, R₅ is selected from H and substituted acyclicalkyl, preferably wherein said acyclic alkyl is substituted by aryl(including heteroaryl) or CONR₇R₈.

In the compounds of formula (I), R₆, R₇, R₈, R₁₀ and R₁₁ areindependently selected from H, alkyl (including branched and unbranchedalkyl, substituted and unsubstituted alkyl, cyclic and acyclic alkyl)and aryl (including heteroaryl) or where R₇ and R₈ are in any NR₇R₈group R₇ and R₈ may be linked to form a heterocyclic group, or where R₆,R₇ and R₈ are in a (CONR₆NR₇R₈) group, R₆ and R₇ may be linked to form aheterocyclic group.

In the compounds of formula (I), R₉ is selected from alkyl (includingbranched and unbranched alkyl, substituted and unsubstituted alkyl,cyclic and acyclic alkyl) and aryl (including heteroaryl).

Where R₆ to R₁₁ are independently selected from alkyl, preferably R₆ toR₁₁ are selected from C₁₋₆ alkyl, preferably C₁₋₆ saturated alkyl andmore preferably from lower alkyl.

Where R₇ and R₈, or R₆ and R₇, are linked to form a heterocyclic ringsaid heterocyclic ring may be saturated, partially unsaturated oraromatic, and is preferably saturated. Said heterocyclic ring ispreferably a 5, 6 or 7-membered ring, preferably a 5 or 6-membered ring,and may contain one or more firer heteroatom(s) preferably selected fromN, O and S.

In a preferred embodiment, R₁ is NH₂, R₂ is 2-furyl, R₃ and R₄ are H andR₅ is arylmethyl (including heteroarylmethyl).

In a particularly preferred embodiment of the invention, the compound offormula (I) is7-(2-fluorobenzyl)-4-(2-furyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine.

Where chiral the compounds of formula (I) may be in the form of aracemic mixture of pairs of enantiomers or in enantiomerically pureform.

According to a further aspect of the present invention there is provideda method of treating or preventing a disorder in which the blocking ofpurine receptors, particularly adenosine receptors and more particularlyadenosine A_(2A) receptors, may be beneficial, the method comprisingadministration to a subject in need of such treatment an effective doseof a compound of formula (I) or a pharmaceutically acceptable salt orprodrug thereof.

The disorder may be caused by the hyperfunctioning of the purinereceptors.

The present invention may be employed in respect of a human or animalsubject, more preferably a mammal, more preferably a human subject.

The disorders of particular interest are those in which the blocking ofpurine receptors, partiucularly adenosine receptors and moreparticularly adenosine A_(2A) receptors, may be beneficial. These mayinclude movement disorders such as Parkinson's disease, drug-inducedParkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced bypoisoning (for example MPTP, manganese, carbon monoxide) andpost-traumatic Parkinson's disease (punch-drunk syndrome).

Other movement disorders in which the blocking of purine receptors, maybe of benefit include progressive supernuclear palsy, Huntingtonsdisease, multiple system atrophy, corticobasal degeneration, Wilsonsdisease, Hallerrorden-Spatz disease, progressive pallidal atrophy,Dopa-responsive dystonia-Parkinsonism, spasticity or other disorders ofthe basal ganglia which result in abnormal movement or posture. Thepresent invention may also be effective in treating Parkinson's withon-off phenomena; Parkinson's with freezing (end of dose deterioration);and Parkinson's with prominent dyskinesias.

The compounds of formula (I) may be used or administered in combinationwith one or more additional drugs useful in the treatment of movementdisorders, such as L-DOPA or a dopamine agonist, the components being inthe same formulation or in separate formulations for administrationsimultaneously or sequentially.

Other disorders in which the blocking of purine receptors, particularlyadenosine receptors and more particularly adenosine A_(2A) receptors maybe beneficial include acute and chronic pain; for example neuropathicpain, cancer pain, trigeminal neuralgia, migraine and other conditionsassociated with cephalic pain, primary and secondary hyperalgesia,inflammatory pain, nociceptive pain, tabes dorsalis, phantom limb pain,spinal cord injury pain, central pain, post-herpetic pain and HIV pain;affective disorders including mood disorders such as bipolar disorder,seasonal affective disorder, depression, manic depression, atypicaldepression and monodepressive disease; central and peripheral nervoussystem degenerative disorders including corticobasal degeneration,demyelinating disease (multiple sclerosis, disseminated sclerosis),Freidrich's ataxia, motoneurone disease (amyotrophic lateral sclerosis,progressive bulbar atrophy), multiple system atrophy, myelopathy,radiculopathy, peripheral neuropathy (diabetic neuropathy, tabesdorsalis, drug-induced neuropathy, vitamin deficiency), systemic lupuserythamatosis, granulomatous disease, olivo-ponto-cerebellar atrophy,progressive pallidal atrophy, progressive supranuclear palsy,spasticity; schizophrenia and related pyshoses; cognitive disordersincluding dementia, Alzheimers Disease, Frontotemporal dementia,multi-infarct dementia, AIDS dementia, dementia associated withHuntingtons Disease, Lewy body dementia, senile dementia, age-relatedmemory impairment, cognitive impairment associated with dementia,Korsakoff syndrome, dementia pugilans; attention disorders such asattention-deficit hyperactivity disorder (ADHD), attention deficitdisorder, minimal brain dysfunction, brain-injured child syndrome,hyperkinetic reaction childhood, and hyperactive child syndrome; centralnervous system injury including traumatic brain injury, neurosurgery(surgical trauma), neuroprotection for head injury, raised intracranialpressure, cerebral oedema, hydrocephalus, spinal cord injury; cerebralischaemia including transient ischaemic attack, stroke (thromboticstroke, ischaemic stroke, embolic stroke, haemorrhagic stroke, lacunarstroke) subarachnoid haemorrhage, cerebral vasospasm, neuroprotectionfor stroke, peri-natal asphyxia, drowning, cardiac arrest, subduralhaematoma; myocardial ischaemia; muscle ischaemia; sleep disorders suchas hypersomnia and narcolepsy; eye disorders such as retinalischaemia-reperfusion injury and diabetic neuropathy; cardiovasculardisorders such as claudication and hypotension; and diabetes and itscomplications.

According to a further aspect of the present invention there is provideduse of a compound of formula (I) or a pharmaceutically acceptable saltor prodrug thereof in the manufacture of a medicament for the treatmentor prevention of movement disorders in a subject.

According to a further aspect of the invention there is provided amethod of treating or preventing movement disorders comprisingadministration to a subject in need of such treatment an effective doseof a compound of formula (I) or a pharmaceutically acceptable salt orprodrug thereof.

According to a further aspect of the invention there is provided use ofa compound of formula (I) or a pharmaceutically acceptable salt orprodrug thereof in the manufacture of a medicament for neuroprotectionin a subject.

According to a further aspect of the invention there is provided amethod of neuroprotection comprising administration to a subject in needof such treatment an effective dose of a compound of formula (I) or apharmaceutically acceptable salt or prodrug thereof.

The medicament for or method of neuroprotection may be of use in thetreatment of subjects who are suffering from or at risk from aneurodegenerative disorder, such as a movement disorder.

According to a further aspect of the invention, there is provided foruse in therapy a compound of formula (I), or a pharmaceuticallyacceptable salt or prodrug thereof.

According to a further aspect of the invention, there is provided acompound of formula (I), or a pharmaceutically acceptable salt orprodrug thereof, per se, other than:

-   (i) compounds wherein R₂ is selected from pyrrolopyrimidines; and-   (ii) compounds wherein R₁ is selected from methyl, phenyl and    (methyl)phenyl, R₂ is selected from phenyl (substituted or    unsubstituted) and R₅ is selected from methyl and methanesulfonyl,    preferably compounds wherein R₁ is selected from methyl and phenyl    (substituted or unsubstituted), R₂ is selected from phenyl    (substituted or unsubstituted) and R₅ is selected from methyl and    methanesulfonyl, and more preferably wherein R₁ is selected from    methyl and phenyl (substituted or unsubstituted) and R₂ is selected    from phenyl (substituted or unsubstituted).

According to a further aspect of the invention, there is provided acompound of formula (I), or a pharmaceutically acceptable salt orprodrug thereof, per se, wherein R₂ is selected from heteroaryl, otherthan compounds wherein R₂ is selected from pyrrolopyrimidines.

In a preferred embodiment, there is provided a compound of formula (I),or a pharmaceutically acceptable salt or prodrug thereof, per se,wherein R₂ is selected from 5- or 6-membered monocyclic heteroarylgroups.

According to a further aspect of the invention, there is provided amethod of preparing the novel compounds of the present invention.Compounds of formula (I) may be prepared according to conventionalsynthetic methods, such as set out in Reaction Scheme 1.

Compounds of formula (1) where R₁ is alkoxy, aryloxy, alkylthio,arylthio, CN or NR₇R₈ may be prepared from compounds of formula (2) bystandard methods such as nucleophilic displacement using an appropriatenucleophilic reagent such as an alcohol, thiol, cyanide or amine(HNR₇R₈) in the presence of a suitable base if required.

Compounds of formula (1) where R₁ is NR₆COR₇, NR₆CO₂R₉ or NR₆SO₂R₉,wherein R₆ is H, alkyl or aryl, may be prepared from compounds offormula (1) where R₁ is NR₇R₈, wherein R₇ is H and R₈ is H, alkyl oraryl, by standard methods such as treatment with an appropriate acidchloride (R₇COCl), chloroformate (ClCO₂R₉) or sulphonyl chloride(R₉SO₂Cl) in the presence of a suitable base such as triethylamine.

Compounds of formula (1) where R₁ is NR₆CONR₇R₈ wherein R₆ is H, alkylor aryl, may be prepared from compounds of formula (1) where R₁ isNR₇R₈, wherein R₇ is H and R₈ is H, alkyl or aryl, by standard methodssuch as treatment with an appropriate isocyanate (R₇NCO or R₈NCO) orcarbamoyl chloride (R₇R₈NCOCl) in the presence of a suitable base suchas triethylamine if required.

Compounds of formula (1) where R₁ is NH₂ may be prepared from compoundsof formula (1) where R₁ is NR₇R₈, wherein R₇ is H and Rs is a suitableprotecting group such as a 3,4-dimethoxybenzyl group, by standardmethods such as treatment with TFA.

Compounds of formula (2) where R₅ is alkyl (including arylalkyl,heteroarylalkyl and (CR₁₀R₁₁)_(n)R₁₂) may be prepared from a compound offormula (3) by standard methods such as reaction with an appropriatealkyl halide, or substituted alkyl halide in the presence of a suitablebase such as sodium hydride.

Compounds of formula (2) where R₅ is (CR₁₀R₁₁)_(n)R₁₂ and R₁₂ is CONR₇R₈or CONR₆NR₇R₈ may be prepared from compounds of formula (2) where R₅ is(CR₁₀R₁₁)_(n)R₁₂ and R₁₂ is CO₂R₆ by standard methods such as directreaction with an appropriate amine or hydrazine or by initial hydrolysisof the ester group CO₂R₆ to a carboxylic acid followed by reaction withan appropriate amine or hydrazine in the presence of a standard couplingreagent such as DCC.

Compounds of formula (2) where R₅ is (CR₁₀R₁₁)_(n)R₁₂, wherein R₁₂ isC(═NR₆)NR₇R₈ may be prepared from compounds of formula (2) where R₅ is(CR₁₀R₁₁)_(n)R₁₂ wherein R₁₂ is CN by standard methods such as treatmentwith an appropriate amine in the presence of trimethyl aluminium.

Compounds of formula (2) where R₅ is (CR₁₀R₁₁)_(n)R₁₂, wherein R₁₂ isCO₂R₆ or CN may be prepared from compounds of formula (3) by standardmethods such as treatment with an appropriate substituted alkyl halidein the presence of a suitable base such as sodium hydride.

Compounds of formula (2) where R₅ is CONR₇R₈ or CONR₆NR₇R₈ may beprepared from compounds of formula (3) by standard methods such astreatment with an appropriate isocyanate (R₇NCO or R₈NCO) or carbamoylchloride (R₇R₈NCOCl or R₇R₈NR₆NCOCl).

Compounds of formula (2) where R₅ is COR₆, CO₂R₉ or SO₂R₉ may beprepared from compounds of formula (3) by standard methods such astreatment with an appropriate acid chloride (R₆COCl), chloroformate(ClCO₂R₉) or sulphonyl chloride (R₉SO₂Cl) in the presence of a suitablebase such as triethylamine.

Compounds of formula (3) are prepared from compounds of formula (4) bystandard methods such as aryl or heteroaryl coupling reactions. Suitablearyl or heteroaryl coupling reactions would include reaction with anappropriate aryl or heteroaryl trialkylstannane derivative, an aryl orheteroarylboronic acid or boronic ester derivative, or an aryl orheteroarylzinc halide derivative in the presence of a suitable catalystsuch as a palladium complex. Compounds of formula (4) are either knownin the literature or are prepared by methods which are analogous tothose described in the literature.

In certain cases it may be advantageous to prepare a compound of formula(2) where R₅ is selected to perform the function of a protecting group,for example a suitable protecting group would be a benzyl group orsubstituted benzyl group such as a 3,4dimethoxybenzyl group or atrimethylsilylethoxymethyl group. Compounds of this nature may preparedas described above and converted to compounds of formula (1), where R₅is a protecting group, as described above. The protecting group R₅ maybe then be removed by standard methods such as treatment with, forexample, TFA or tetra-n-butylammonium fluoride to give a compound offormula (1) where R₅ is H. Compounds of formula (1) where R₅ is H maythen be used to prepare other compounds of formula (1), where R₅ is aspreviously defined, by the methods described above.

In certain cases it may be advantageous to prepare compounds of formula(1) where R₅ is alkyl (including arylalkyl, heteroarylalkyl and(CR₁₀R₁₁)_(n)R₁₂ from compounds of formula (1) where R₅ is H by themethods described above.

Other compounds of formula (1) may be prepared by standard methods suchas those illustrated in Reaction Scheme 2.

Compounds of formula (1) where R₁ is alkyl or aryl may be prepared fromcompounds of formula (5) where R₁ is alkyl or aryl by standard methodssuch as aryl or heteroaryl coupling reactions as described above.Compounds of formula (5) where R₁ is alkyl or aryl are either known inthe literature or may be prepared by methods analogous to thosedescribed in the literature.

Compounds of formula (1) where R₃ and R₄ are H, alkyl, halogen, alkoxy,alkylthio, CN or NR₇R₈ may be prepared by the methods described above.Suitable intermediates such as compounds of formula (4) and (5) where R₃and R₄ are as described above, are either known in the literature or areprepared by methods which are analogous to those described in theliterature.

According to a further aspect of the invention, there is provided apharmaceutical composition comprising a compound of formula (I) incombination with a pharmaceutically acceptable carrier or excipient anda method of making such a composition comprising combining a compound offormula (I) with a pharmaceutically acceptable carrier or excipient.

The pharmaceutical compositions employed in the present inventioncomprise a compound of formula (I), or pharmaceutically acceptable saltsor prodrugs thereof, and may also contain a pharmaceutically acceptablecarrier and optionally other therapeutic ingredients known to thoseskilled in the art. The term, “pharmaceutically acceptable salts”,refers to salts prepared from pharmaceutically acceptable non-toxicacids including inorganic acids and organic acids.

Where the compounds of formula (I) are basic, salts may be prepared frompharmaceutically acceptable non-toxic acids including inorganic andorganic acids. Such acids include acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic,hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic andthe like. Particularly preferred are hydrochloric, hydrobromic,phosphoric, and sulfuric acids, and most particularly preferred is thehydrochloride salt.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of a compound of formula (I). Forexample, oral, rectal, parenteral (intravenous, intramuscular),transdermal, subcutaneous, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,patches, and the like. The most suitable route in any given case willdepend on the severity of the condition being treated. The mostpreferred route of administration of the present invention is the oralroute. The compositions may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

In practical use, the compounds of formula (I) can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g. oral or parenteral (e.g.intravenous). In preparing the compositions for oral dosage form, any ofthe usual pharmaceutical media may be employed as carriers, such as, forexample, water, glycols, oils, alcohols, flavouring agents,preservatives, colouring agents, and the like in the case of oral liquidpreparations (such as suspensions, solutions and elixirs) or aerosols;or carriers such as starches, sugars, micro-crystalline cellulose,diluents, granulating agents, lubricants, binders, disintegratingagents, and the like may be used in the case of oral solid preparationssuch as, for example, powders, capsules, and tablets, with the solidoral preparations being preferred over the liquid preparations. The mostpreferred solid oral preparation is tablets.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form in which case solidpharmaceutical carriers are employed. If desired, tablets may be coatedby standard aqueous or non-aqueous techniques.

In addition to the common dosage forms set out above, the compounds offormula (I) may also be administered by controlled release means and/ordelivery devices such as those described in U.S. Pat. Nos.: 3,845,770;3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; 4,687,660; and4,769,027, the disclosures of which are hereby incorporated byreference.

Pharmaceutical compositions employed in the present invention suitablefor oral administration may be presented as discrete units such ascapsules, cachets, or tablets, or aerosol sprays each containing apredetermined amount of the active ingredient as a powder or granules, asolution or a suspension in an aqueous liquid, an oil-in-water emulsion,or a water-in-oil liquid emulsion. Such compositions may be prepared byany of the methods of pharmacy, but all methods include the step ofbringing the active ingredient into association with the carrier whichconstitutes one or more necessary ingredients. In general, thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation.

For example, a tablet may be prepared by compression or moulding,optionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, a lubricant, an inert diluent, and/or a surfaceactive or dispersing agent. Moulded tablets may be made by moulding in asuitable machine a mixture of the powdered compound moistened with aninert liquid diluent.

The invention is further defined by reference to the following examples.It will be apparent to those skilled in the art that many modifications,both to materials and methods, may be practised without departing fromthe purpose and interest of this invention.

EXAMPLES Synthetic Examples

The invention is illustrated with reference to the following Examples,as set out in Table 1.

TABLE 1 Example Structure Compound Name 1

N,N-dimethyl-4-(2-furyl)-1H-pyrrolo[2,3-d]pyrimidine-2-amine 2

2-chloro-4-(2-furyl)-1H-pyrrolo[2,3-d]pyrimidine 3

7-benzyl-N,N-dimethyl-4-(2-furyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine 4

7-benzyl-2-chloro-4-(2-furyl)-7H-pyrrolo[2,3-d]pyrimidine 5

7-benzoyl-N,N-dimethyl-4-(2-furyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine 6

(2R)-2-(2-hydroxymethylpyrrolidin-1-yl)-4-(2-furyl)-1H-pyrrolo[2,3-d]pyrimidine7

N-(3,4-dimethoxybenzyl)-4-(2-furyl)-1H-pyrrolo[2,3-d]pyrimidine-2-amine8

4-(2-furyl)-1H-pyrrolo[2,3-d]pyrimidine-2-amine 9

N-benzyl-N′-(4-(2-furyl)-1H-pyrrolo[2,3-d]pyrimidin-2-yl)urea 10

2-chloro-7-(2-fluorobenzyl)-4-(2-furyl)-7H-pyrrolo[2,3-d]pyrimidine 11

N,N-dimethyl-7-(2-fluorobenzyl)-4-(2-furyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine12

N-(3,4-dimethoxybenzyl)-7-(2-fluorobenzyl)-4-(2-furyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine13

7-(2-fluorobenzyl)-4-(2-furyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine

The syntheses of the above Examples is described with reference to thefollowing general synthetic Methods. The analytical data for theExamples, together with the Method of synthesis used is given in Table2.

Synthetic Methods Method A2-Chloro-4-(2-furyl)-1H-pyrrolo[2,3-d]pyrimidin (Example 2)

A solution of 2,4-dichloro-1H-pyrrolo[2,3-d]pyrimidine (4.1 g, 21.8mmol) in DMF (20 mL) was treated with PdCl₂(PPh₃)₂ (772 mg, 0.17 mmol)and 2-(tributylstannyl)-furan (6.9 mL, 21.8 mmol), stirred at roomtemperature for 16 h, diluted with diethyl ether and filtered to givethe title compound (2.94 g, 61%) as a pale orange solid.

Method B2-chloro-7-(2-fluorobenzyl)-4-(2-furyl)-7H-pyrrol[2,3-d]pyrimidine(Example 10)

A solution of 2-chloro-4-(2-furyl)-1H-pyrrolo[2,3-d]pyrimidine (219 mg,1 mmol) in DMF (2 mL) at 0° C. was treated with NaH (40 mg, 60%, 1mmol), stirred for 20 min, treated with 2-fluorobenzyl bromide (120 μL,1 mmol), stirred at room temperature for 1 h, quenched with water,extracted with EtOAc, dried (MgSO₄), concentrated in vacuo and purifiedby chromatography (EtOAc:Heptane, 1:4) to give the title compound (250mg, 76%) as a cream solid.

Method CN-(3,4-dimethoxybenzyl)-7-(2-fluorobenzyl)-4-(2-furyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine(Example 12)

A solution of2-chloro-7-(2-fluorobenzyl)4(2-furyl)-7H-pyrrolo[2,3-d]pyrimidine (254mg, 0.78 mmol) in N-methylpyrrolidone (2 mL) was treated withveratrylamine (0.25 mL, 1.66 mmol), heated to 100° C. for 16 h andpurified by chromatography (Heptane:EtOAc, 4:1) to give the titlecompound (316 mg, 88%) as a cream solid.

Method D7-(2-fluorobenzyl)-4-(2-furyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine(Example 13)

A solution ofN-(3,4-dimethoxybenzyl)-7-(2-fluorobenzyl)4-(2-furyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine(110 mg, 0.24 mmol) in TFA (1 mL) was heated to 50° C. for 3 h,concentrated in vacuo, treated with saturated NaHCO₃, extracted withEtOAc, dried (MgSO₄), concentrated in vacuo, purified by chromatography(EtOAc:Heptane, 1:4) and recrystallised (EtOAc) to give the titlecompound (38 mg, 51%) as a cream solid.

Method E7-Benzoyl-N,N-dimethyl-4-(2-furyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine(Example 5)

A solution ofN,N-dimethyl-4-(2-furyl)-1H-pyrrolo[2,3-d]pyrimidine-2-amine (181 mg,0.8 mmol) in THF (3 mL) was treated with Et₃N, (111 μL, 0.8 mmol),benzoyl chloride (93 μL, 0.8 mmol) and a catalytic amount of DMAP,stirred at room temperature for 16 h, quenched with water, extractedwith EtOAc, dried (MgSO₄), concentrated in vacuo and purified bychromatography (EtOAc:Heptane, 1:9 then Heptane:DCM, 2:1) to give thetitle compound (76 mg) as a yellow solid.

Method F N-benzyl-N′-(4-(2-furyl)-1H-pyrrolo[2,3-d]pyrimidin-2-yl)urea(Example 9)

A solution of 4-(2-furyl)-1H-pyrrolo[2,3-d]pyrimidine-2-amine (192 mg,0.96 mmol) in THF (3 mL) was treated with benzyl isocyanate (118 μL,0.96 mmol), stirred at room temperature for 16 h and the resulting solidfiltered and washed with EtOAc to give the title compound (61 mg, 19%)as a yellow solid.

Method G2,4-Dichloro-7-(2-trimethylsilylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine

A solution of 2,4-dichloro-1H-pyrrolo[2,3-d]pyrimidine (542 mg, 2.58mmol) in MeCN (20 mL) was treated with NaH (113 mg, 2.84 mmol), stirredfor 1 h, treated with trimethylsilylethyl chloride (502 μL, 2.84 mmol),stirred at room temperature for 3 h, poured into water, extracted withEtOAc, dried (MgSO₄) and concentrated in vacuo to give the titlecompound (913 mg, 104%) which was used crude in the next reaction.

Method H N,N-Dimethyl-4-(2-furyl)-1H-pyrrolo[2,3-d]pyrimidine-2-amine(Example 1)

A solution ofN,N-dimethyl4-(2-furyl)-7-(2-trimethylsilylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine(370 mg, 0.97 mmol) in THF (3 mL) was treated with tetrabutylammoniumfluoride (1 ml, 1-M in THF, 1 mmol), refluxed for 36 h, poured intowater, extracted with EtOAc, dried (MgSO₄), concentrated in vacuo andpurified by chromatography (EtOAc:Heptane, 1:9, alumina) to give thetitle compound (47 mg, 21%) as a yellow solid.

2-Chloro-4-(2-furyl)-7-(2-trimethylsilylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine

This was prepared from2,4-dichloro-7-(2-trimethylsilylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidineby method A and the title compound (207 mg, 21%) isolated as a creamsolid.

N,N-Dimethyl-4-(2-furyl)-7-(2-trimethylsilylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine

This was prepared from2-chloro-4-(2-furyl)-7-(2-trimethylsilylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidineby method C and the title compound (409 mg, 77%) isolated as a whitesolid.

TABLE 2 Yield Example Method (%) Physical Data 1 H 21 mp 196.9–197.1 °C.; NMR δ_(H) (400 MHz, CDCl₃) 3.27 (6H, s), 6.57– 6.60 (1H, m),6.83–6.86 (1H, m), 6.93– 6.97 (1H, m), 7.31 (1H, d, J 4.0 Hz), 7.65–7.68(1H, m), 8.84 (1H, s) 2 A 61 mp 265.8–266.3 ° C.; IR ν_(max)(Nujol)/cm⁻¹ 3199, 3108, 2924, 2854, 1593, 1530 and 1462; NMR _(H) (400MHz, DMSO) 6.79–6.82 (1H, m), 6.98–6.99 (1H. m), 7.50 (1H, d, J 3.5 Hz),7.67 (1H, t, J 3.5 Hz), 8.08 (1H, d. J 1.0 Hz), 12.4 (1H, s) 3 B mp91.7–92.3 ° C.; IR ν_(max) (Nujol)/cm⁻¹ 3020, 2924, 2854, 1613, 1582,1542, 1452, 1395 and 733 ; NMR_(δH) (400 MHz, CDCl₃) 3.27 (6H, s), 5.31(2H, s), 6.55–6.57 (1H, m), 6.80 (1H, d, J 3.5 Hz), 6.81 (1H, d, J 4.0Hz), 7.23–7.34 (6H, m), 7.63–7.65 (1H, m); 4 B IR ν_(max) (Nujol)/cm⁻¹3116, 3064, 3032, 2931, 1600, 1565, 1509, 1328, 1256, 1151 and 920; NMRδ_(H) (400 MHz, CDCl₃) 5.43 (2H, s), 6.61– 6.65 (1H, m), 7.01 (1H, d, J3.5 Hz), 7.15 (1H, d, J 3.5 Hz), 7.21–7.37 (5H, m), 7.47 (1H, dd, J 3.5,1.0 Hz), 7.69–7.71 (1H, m) 5 E mp 108.3–109.1 ° C.; NMR δ_(H) (400 MHz,CDCl₃) 2.89 (6H, s), 6.57– 6.60 (1H, m), 7.05 (1H, d, J 4.0 Hz),7.28–7.29 (1H, m), 7.43–7.48 (2H, m), 7.53–7.59 (2H, m), 7.66–7.67 (1H,m), 7.75–7.79 (2H, m); Anal. Calcd for C₁₉H₁₆N₄O₂ + 0.3 H₂O: C, 67.56;H, 4.95, N, 16.59. Found: C, 67.48; H, 4.72; N, 16.45; .M/Z 333 (M +H)⁺. 6 C 64 mp 174.8–175.6 ° C.; IR ν_(max) (Nujol)/cm⁻¹ 3094, 2752,1611, 1560, 1518 and 1467; NMR δ_(H) (400 MHz, DMSO) 1.81–2.04 (2H, m),3.26–3.36 (2H, m), 3.56–3.47 (1H, m), 3.47–3.62 (2H, m), 3.69–3.76 (1H,m), 4.11–4.24 (1H, m), 5.01 (1H, s), 6.66–6.69 (1H, m), 6.71–6.74 (1H,m), 7.11 (1H, dd, J 3.5, 2.0 Hz), 7.30 (1H, dd, J 3.5, 1.0 Hz),7.96–7.97 (1H, m), 11.41 (1H, s). 7 C 82 mp 154.8–154.9 ° C.; IR ν_(max)(Nujol)/cm⁻¹ 3459, 3416, 3142, 1623, 1593, 1482, 1467, 1266 and 742; NMRδ_(H) (400 MHz, DMSO) 3.69 (3H, s), 3.71 (3H, s), 4.47 (2H, d, J 6.0Hz), 6.65–6.67 (1H, m), 6.71– 6.72 (1H, m), 6.83–6.91 (2H, m), 7.03–7.09(3H, m), 7.27 (1H, d, J 2.5 Hz), 7.94–7.96 (1H, m), 11.27 (1H, s); Anal.Calcd for C₁₉H₁₈N₄O₃ + 2 H₂O: C, 59.06; H, 5.749, N, 14.50. Found: C,59.07; H, 5.74; N, 14.19. 8 D 83 mp 213.5–214.5 ° C.; IR ν_(max)(Nujol)/cm⁻¹ 3448, 3287, 3188, 3133, 3069, 2924, 2854, 1625, 1556 and1468; NMR δ_(H) (400 MHz, DMSO) 6.10 (2H, s), 6.64–6.67 (1H, m),6.69–6.71 (1H, m), 7.09 (1H, dd, J 3.5, 2.5 Hz), 7.21–7.24 (1H, d, 72.5Hz), 7.95 (1H, s), 11.22 (1H, s). 9 F 19 IR ν_(max) (Nujol)/cm⁻¹ 3208,3140, 2730, 1668, 1603, 1557, 1463, 1376 and 1363; NMR δ_(H) (400 MHz,DMSO) 4.51 (2H, d, J 5.5 Hz), 6.68– 6.70 (1H, m), 6.82–6.85 (1H, m),7.07 (1H, d, J 3.5 Hz), 7.27–7.33 (1H, m), 7.35–7.44 (5H, m), 7.95 (1H,d, J 1.0 Hz), 9.42 (1H, s), 9.86 (1H, t, J 5.5 Hz), 11.88 (1H, s). 10 B76 mp 126.8–127.1 ° C.; IR ν_(max) (Nujol)/cm⁻¹ 2923, 2854, 1601, 1547,1458, 1376, 1256, 920 and 733; NMR δ_(H) (400 MHz, DMSO) 5.52 (2H, s),6.80–6.83 (1H, m), 7.06 (1H, d, J 3.5 Hz), 7.10–7.19 (2H, m), 7.22– 7.28(1H, m), 7.35–7.41 (1H. m), 7.52 (1H, d, J 3.5 Hz), 7.71 (1H, d, J 3.5Hz), 8.10 (1H, s); Anal. Calcd for C₁₇H₁₁ClN₃O + 0.25 H₂O: C, 61.46; H,3.49, N, 12.65. Found: C, 61.31; H, 3.31; N, 12.37. 11 C 86 mp115.1–115.2 ° C.; NMR δ_(H) (400 MHz, DMSO) 3.18 (6H, s), 5.35 (2H, s),6.70–6.75 (2H, m), 7.10–7.27 (4H, m), 7.30–7.38 (2H, m), 7.97 (1H, s);Anal. Calcd for C₁₉H₁₇FN₄O + 0.1 H₂O: C, 67.48; H, 5.13, N, 16.57.Found: C, 67.51; H, 5.10; N, 16.13; M/Z 336 M⁺. 12 C 88 IR ν_(max)(Nujol)/cm⁻¹ 3252, 3112, 2924, 2854, 1582, 1515 and 1464; NMR δ_(H) (400MHz, DMSO) 3.67 (3H, s), 3.69 (3H, s), 4.46 (2H, d, J 6.5 Hz), 5.33 (2H,s), 6.69–6.75 (2H, m), 6.79 (1H, d, J 8.5 Hz), 6.89 (1H, d, J 8.0 Hz),6.97–7.09 (3H, m), 7.14–7.37 (5H, m), 7.96 (1H, s); Anal. Calcd forC₂₆H₂₃FN₄O₃: C, 68.11; H, 5.06, N, 12.21. Found: C, 68.14; H, 5.08; N,12.20. 13 D 51 IR ν_(max) (Nujol)/cm⁻¹ 3329, 3193, 2924, 1649, 1577 and1552; NMR δ_(H) (400 MHz, DMSO) 5.34 (2H, s), 6.26 (2H, s), 6.70–6.73(1H, m), 6.77 (1H, d, J 3.5 Hz), 6.95 (1H, t, J 8.0 Hz), 7.09–7.18 (2H,m), 7.19–7.28 (2H, m), 7.30–7.37 (1H, m), 7.96 (1H, s).

Adenosine Receptor Binding

Binding Affinities at hA_(2A) Receptors

The compounds were examined in an assay measuring in vitro binding tohuman adenosine A_(2A) receptors by determining the displacement of theadenosine A_(2A) receptor selective radioligand [³H]-CGS 21680 usingstandard techniques. The results are summarised in Table 3.

TABLE 3 Example K_(i)(nM) Example 1 60 Example 8 272 Example 13 16

Evaluation of Potential Anti-Parkinsonian Activity in Vivo

Haloperidol-induced Hypolocomotion Model

It has previously been demonstrated that adenosine antagonists, such astheophylline, can reverse the behavioural depressant effects of dopamineantagonists, such as haloperidol, in rodents (Mandhane S. N. et al.,Adenosine A₂ receptors modulate haloperidol-induced catalepsy in rats.Eur. J. Pharmacol. 1997, 328, 135–141). This approach is also considereda valid method for screening drugs with potential antiparkinsonianeffects. Thus, the ability of novel adenosine antagonists to blockhaloperidol-induced deficits in locomotor activity in mice can be usedto assess both in vivo and potential antiparkinsonian efficacy.

Method

Female TO mice (25–30 g) obtained from TUCK, UK, are used for allexperiments. Animals are housed in groups of 8 [cage size−40 (width)×40(length)×20 (height)cm] under 12 hr light/dark cycle (lights on 08:00hr), in a temperature (20±2° C.) and humidity (55±15%) controlledenvironment. Animals have free access to food and water, and are allowedat least 7 days to acclimatize after delivery before experimental use.

Drugs

Liquid injectable haloperidol (1 ml Serenance ampoules from BakerNorton, Harlow, Essex, each containing haloperidol BP 5 mg, batch #P424) are diluted to a final concentration of 0.02 mg/ml using saline.Test compounds are typically prepared as aqueous suspensions in 8%Tween. All compounds are administered intraperitoneally in a volume of10 ml/kg.

Procedure

1.5 hours before testing, mice are administered 0.2 mg/kg haloperidol, adose that reduces baseline locomotor activity by at least 50%. Testsubstances are typically administered 5–60 minutes prior to testing. Theanimals are then placed individually into clean, clear polycarbonatecages [20 (width)×40 (length)×20 (height) cm, with a flat perforated,Perspex lid]. Horizontal locomotor activity is determined by placing thecages within a frame containing a 3×6 array of photocells linked to acomputer, which tabulates beam breaks. Mice are left undisturbed toexplore for 1 hour, and the number of beams breaks made during thisperiod serves as a record of locomotor activity which is compared withdata for control animals for statistically significant differences.

6-OHDA Model

Parkinson's disease is a progressive neurodegenerative disordercharacterised by symptoms of muscle rigidity, tremor, paucity ofmovement (hypokinesia), and postural instability. It has beenestablished for some time that the primary deficit in PD is a loss ofdopaminergic neurones in the substantia nigra which project to thestriatum, and indeed a substantial proportion of striatal dopamine islost (ca 80–85%) before symptoms are observed. The loss of striataldopamine results in abnormal activity of the basal ganglia, a series ofnuclei which regulate smooth and well co-ordinated movement (Blandini F.et al., Glutamate and Parkinson's Disease. Mol. Neurobiol. 1996, 12,73–94). The neurochemical deficits seen in Parkinson's disease can bereproduced by local injection of the dopaminergic neurotoxin6-hydroxydopamine into brain regions containing either the cell bodiesor axonal fibres of the nigrostriatal neurones.

By unilaterally lesioning the nigrostriatal pathway on only one-side ofthe brain, a behavioural asymmetry in movement inhibition is observed.Although unilaterally-lesioned animals are still mobile and capable ofself maintenance, the remaining dopamine-sensitive neurones on thelesioned side become supersenstive to stimulation. This is demonstratedby the observation that following systemic administration of dopamineagonists, such as apomorphine, animals show a pronounced rotation in adirection contralateral to the side of lesioning. The ability ofcompounds to induce contralateral rotations in 6-OHDA lesioned rats hasproven to be a sensitive model to predict drug efficacy in the treatmentof Parkinson's Disease.

Animals

Male Sprague-Dawley rats, obtained from Charles River, are used for allexperiments. Animals are housed in groups of 5 under 12 hr light/darkcycle (lights on 08:00 hr), in a temperature (20±2° C.) and humidity(55±15%) controlled environment. Animals have free access to food andwater, and are allowed at least 7 days to acclimatize after deliverybefore experimental use.

Drugs

Ascorbic acid, desipramine, 6-OHDA and apomorphine (Sigma-Aldrich,Poole, UK). 6-OHDA is freshly prepared as a solution in 0.2% ascorbateat a concentration of 4 mg/mL prior to surgery. Desipramine is dissolvedin warm saline, and administered in a volume of 1 ml/kg. Apomorphine isdissolved in 0.02% ascorbate and administered in a volume of 2 mL/kg.Test compounds are suspended in 8% Tween and injected in a volume of 2mL/kg.

Surgery

15 minutes prior to surgery, animals are given an intraperitonealinjection of the noradrenergic uptake inhibitor desipramine (25 mg/kg)to prevent damage to non-dopamine neurones. Animals are then placed inan anaesthetic chamber and anaesthetised using a mixture of oxygen andisoflurane. Once unconscious, the animals are transferred to astereotaxic frame, where anaesthesia is maintained through a mask. Thetop of the animal's head is shaved and sterilised using an iodinesolution. Once dry, a 2 cm long incision is made along the midline ofthe scalp and the skin retracted and clipped back to expose the skull. Asmall hole is then drilled through the skill above the injection site.In order to lesion the nigrostriatal pathway, the injection cannula isslowly lowered to position above the right medial forebrain bundle at−3.2 mm anterior posterior, −1.5 mm medial lateral from bregma, and to adepth of 7.2 mm below the duramater. 2 minutes after lowing the cannula,2 μL of 6-OHDA is infused at a rate of 0.5 μL/min over 4 minutes,yeilding a final dose of 8 μg. The cannula is then left in place for afurther 5 minutes to facilitate diffusion before being slowly withdrawn.The skin is then sutured shut using Ethicon W501 Mersilk, and the animalremoved from the strereotaxic frame and returned to its homecage. Therats are allowed 2 weeks to recover from surgery before behaviouraltesting.

Apparatus

Rotational behaviour is measured using an eight station rotameter systemprovided by Med Associates, San Diego, USA. Each station is comprised ofa stainless steel bowl (45 cm diameter×15 cm high) enclosed in atransparent Plexiglas cover running around the edge of the bowl, andextending to a height of 29 cm. To assess rotation, rats are placed incloth jacket attached to a spring tether connected to optical rotameterpositioned above the bowl, which assesses movement to the left or righteither as partial (45°) or full (360°) rotations. All eight stations areinterfaced to a computer that tabulated data.

Procedure

To reduce stress during drug testing, rats are initially habituated tothe apparatus for 15 minutes on four consecutive days. On the test day,rats are given an intraperitoneal injection of test compound 30 minutesprior to testing. Immediately prior to testing, animals are given asubcutaneous injection of a subthreshold dose of apomorphine, thenplaced in the harness and the number of rotations recorded for one hour.The total number of full contralatral rotations during the hour testperiod serves as an index of antiparlinsonian drug efficacy.

1. A compound of formula (I):

wherein R₁ is selected from the group consisting of alkyl, alkoxy,aryloxy, alkylthio, arylthio, aryl, halogen, CN, NR₇R₈, NR₆COR₇,NR₆CONR₇R₈, NR₆CO₂R₉, and NR₆SO₂R₉; R₂ is a heteroaryl, attached via anunsaturated ring carbon of said heteroaryl group, other thanpyrrolopyrimidine; R₃ and R₄ are independently selected from the groupconsisting of H, alkyl, halogen, alkoxy, alkylthio, CN, and NR₇R₈; R₅ isselected from the group consisting of H, acyclic alkyl, COR₆, CONR₇R₈,CONR₆NR₇R₈, CO₂R₉, and SO₂R₉; R₆, R₇, and R₈ are independently selectedfrom the group consisting of H, alkyl, and aryl, or where R₇ and R₈ arein an NR₇R₈ group R₇ and R₈ may be linked to form a heterocyclic group,or where R₆, R₇, and R₈ are in a (CONR₆NR₇R₈) group, R₆ and R₇ may belinked to form a heterocyclic group; and R₉ is selected from alkyl andaryl, or a pharmaceutically acceptable salt thereof.
 2. The compound ofclaim 1, wherein R₁ is selected from the group consisting of alkyl,alkoxy, thioalkyl, NR₇R₈, NR₆COR₇, NR₆CONR₇R₈, NR₆CO₂R₉, and NR₆SO₂R₉.3. The compound of claim 1, wherein R₁ is selected from the groupconsisting of NR₇R₈, NR₆COR₇NR₆CONR₇R₈, NR₆CO₂R₉, and NR₆SO₂R₉.
 4. Thecompound of claim 1, wherein R₁ is NR₇R₈.
 5. The compound of claim 1,wherein R₁ is NH₂.
 6. The compound of claim 1, wherein R₁ is selectedfrom the group consisting of NR₆COR₇, NR₆CONR₇R₈, NR₆CO₂R₉ and NR₆SO₂R₉,and R₆ is H or alkyl.
 7. The compound of claim 1, wherein R₁ is selectedfrom the group consisting of NR₆COR₇, NR₆CONR₇R₈, NR₆CO₂R₉ and NR₆SO₂R₉,and R₆ is H.
 8. The compound of claim 1, wherein R₁ is selected from thegroup consisting of haloalkyl and arylalkyl.
 9. The compound of claim 1,wherein R₂ is a 5- or 6-membered monocyclic heteroaryl group.
 10. Thecompound of claim 1, wherein R₂ is unsubstituted in at least one orthoposition.
 11. The compound of claim 1, wherein R₂ is unsubstituted atboth ortho positions.
 12. The compound of claim 1, wherein R₂ is aheteroaryl group which is attached to the pyrimidine ring of formula (I)such that a heteroatom is adjacent to said unsaturated carbon atomattached to the pyrimidine ring.
 13. The compound of claim 1, wherein R₂is an N, O or S-containing heteroaryl group.
 14. The compound of claim1, wherein R₂ is selected from the group consisting of furyl, thienyl,pyridyl, pyrazolyl and thiazolyl.
 15. The compound of claim 1, whereinR₂ is selected from the group consisting of 2-furyl, 2-thienyl,2-thiazolyl, 3-pyrazolyl, and 2-pyridyl.
 16. The compound of claim 1,wherein R₃ is hydrogen.
 17. The compound of claim 1, wherein R₄ ishydrogen.
 18. The compound of claim 1, wherein R₅ is selected from thegroup consisting of H and substituted acyclic alkyl.
 19. The compound ofclaim 18, wherein R₅ is acyclic alkyl substituted by a substituentselected from the group consisting of aryl, cycloalkyl, non-aromaticheterocyclyl, CO₂R₆, CONR₇R₈, CONR₆NR₇R₈, and C(═NR₆)NR₇R₈.
 20. Thecompound of claim 19, wherein R₅ is acyclic alkyl substituted by aryl orCONR₇R₈.
 21. The compound of claim 20, wherein R₅ is methyl substitutedby aryl or CONR₇R₈.
 22. The compound of claim 1, wherein R₅ is(CR₁₀R₁₁)_(n)R₁₂, wherein: n is 1 to 6, R₁₀ and R₁₁ are independentlyselected from H, alkyl, and aryl, and R₁₂ is selected from the groupconsisting of substituted and unsubstituted aryl, cycloalkyl,non-aromatic heterocyclic, CO₂R₆, CONR₇R₈, CONR₆NR₇R₈, and C(═NR₆)NR₇R₈.23. The compound of claim 22, wherein n is
 1. 24. The compound of claim22, wherein R₁₀ and R₁₁ are independently selected from H and alkyl. 25.The compound of claim 22, wherein R₁₂ is selected from aryl and CONR₇R₈.26. The compound of claim 22, wherein R₁₂ is selected from mono-, di- ortri-substituted aryl groups represented by the formulaAr(R₁₃)_(a)(R₁₄)_(b)(R₁₅)_(c) wherein: Ar is an aryl group; R₁₃R₁₄ andR₁₅ are substituent group(s), the same or different; and a, b and c are0 or 1 such that a+b+c≧1.
 27. The compound of claim 25, wherein saidaryl group is selected from the group consisting of phenyl, thienyl,furyl, indolyl and pyridyl.
 28. The compound of claim 25, wherein R₁₃,R₁₄ and R₁₅ are independently selected from the group consisting ofNR₇R₈, alkyl, alkoxy, halogen, NO₂, CN, hydroxy, NHOH, CHO, CONR₇R₈,CO₂R₇, NR₆COR₇, NR₆CO₂R₉, NR₆SO₂R₉, OCO₂R₉, and aryl.
 29. The compoundof claim 28, wherein R₁₃, R₁₄ and R₁₅ are independently selected fromthe group consisting of NR₇R₈, alkyl, and halogen.
 30. The compound ofclaim 28, wherein R₁₃, R₁₄ and R₁₅ are independently selected from asubstituted alkyl, wherein said substituent is selected from the groupconsisting of alkoxyalkyl, hydroxyalkyl, aminoalkyl, and haloalkyl. 31.The compound of claim 29, wherein R₁₃, R₁₄ and R₁₅ are independentlyselected from the group consisting of NH₂, unsubstituted alkyl, andfluoro.
 32. The compound of claim 22, wherein R₁₂ is CONR₇R₈, R₇ is H,and R₈ is selected from the group consisting of H, unsubstituted alkyl,and arylalkyl.
 33. The compound of claim 1, wherein R₅ is CONR₇R₈, R₇ isH, and R₈ is arylalkyl.
 34. The compound of claim 33, wherein R₈ isarylmethyl.
 35. The compound of claim 1, wherein R₆ to R₁₁ areindependently selected from lower alkyl.
 36. The compound of claim 1,wherein R₁ is NH₂, R₂ is 2-furyl, R₃ and R₄ are H, and R₅ is arylmethyl.37. The compound of claim 1, wherein the compound of formula (I) is7-(2-fluorobenzyl)-4-(2-furyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine.